NACP, the precursor of non-A component of Alzheimer's disease (AD) amyloid (alpha-synuclein) is a synaptic molecule that accumulates in AD plaques. Recent studies have shown that a mutation in NACP is associated with familial Parkinson disease and that Lewy bodies are immunoreactive with antibodies against this molecule. In this context, the central hypothesis of this project is that abnormal accumulation/compartmentalization of NACP is involved in the process of neurodegeneration in Lewy body disease (LBD). The main objective of this proposal is to better understand the mechanisms through which abnormal accumulation of NACP leads to neurodegeneration. For this purpose, we propose the following Specific Aims: 1) To determine the relationship between abnormal NACP/alpha- synuclein accumulation and neurodegeneration in the brains of patients with LBD. We hypothesize that in LBD abnormal accumulation of NACP/alpha- synuclein will result in neurodegeneration of cells within the mesolimbic, mesocortical and striatonigral systems. For this purpose, we propose to determine the relationship between NACP/alpha-synuclein levels in synapses, neurons and neurites and cell counts, synapse density and apoptosis in postmortem brains (frontal, temporal, hippocampus, basal ganglial, cingulate and mesencephalon) from patients with LBD. 2) To develop in vivo models to investigate mechanisms which NACP/alpha- synuclein promotes neurodegeneration. We hypothesize that abnormal NACP/alpha-synuclein accumulation resulting over-expression of NACP/alpha-synuclein will result in synaptic damage and neuronal cell death in transgenic (tg) mice. Furthermore, we postulate that mutant NACP/alpha-synuclein might accelerate this process. For this purpose we propose to investigate the patterns of neurodegeneration in the brains of young and old tg mice over-expressing mutant and wildtype human NACP/alpha-synuclein under the control of the platelet-derived growth factor (PDGF) promoter. 3) To determine if risk factors associated with AD increase susceptibility to NACP/alpha-synuclein-induced neurodegeneration in tg mice. We hypothesize that known genetic risk factors for AD such as the presence of apolipoprotein E4 allele (ApoEepsilon4) and amyloid precursor protein (APP) mutations will enhance NACP/alpha-synuclein tg mice will be crossbred with apoE-deficient (knockout), ApoEepsilon3 or E4 tg mice, and with amyloid precursor protein (APP) wildtype and mutant tg MICE. Taken together these studies will help to better delineate the molecular and cellular mechanisms involved in neurodegeneration in LBD. The models and paradigms developed will also help to identify potential targets that will prevent neuronal cell injury in neurodegenerative disorders.